Demographic characteristics of chronic myeloid leukemia cases and controls

Age distribution

Lower age at onset was observed mostly for Asian countries ranging from 38 to 40 years as compared to the Western population.[10] The mean age at onset of CML patients (36.34 years) (standard deviation: 12.8) observed in the present study showed a similar trend with that of the Asian populations with a range of 7?80 years and median age of 35 years. Lower mean age at onset could be attributed to high prevalence of chronic infections or shorter life expectancy of elderly people after diagnosis.[14] However, in our study, CML was found to be highly prevalent in the age groups of 20?40 years (58.8% with mean age 30.74 ? 6.10) and >40 years (33.8% with mean age 50.73 ? 7.50) [Table 1], confirming that mostly middle-aged people had higher risk to develop CML. With respect to sex, males belonging to the age group >40 years were found to be more frequently affected than females in the same age group (sex ratio 2.43:1).

Environmental factors in conferring risk to chronic myeloid leukemia

Previously, exposure to ionizing radiation was considered as the only risk factor for CML which was evident from increased CML incidence among the survivors of atomic bomb detonations in Hiroshima and Nagasaki [15] and also among the workers of Chernobyl nuclear power plant accident.[1] Electromagnetic field was also considered as one of the risk factors for CML in few reports.[16] [17] Few studies implied various chemicals including pesticides in contributing to a little or moderate risk to CML development.[1] In our study, there were no data on kind and level of exposure to various environmental factors. However, area of living and occupation were considered to evaluate the environmental risk confounding factors in CML development.

Area of living

Higher frequency of patients belonged to rural areas (65.2%) than those residing in the urban regions (34.8%) [Table 1]. This might be attributed to the possible occupational exposure of the people in rural areas to various chemicals including pesticides as most of them were observed to be agricultural laborers. Among CML patients from rural area, the frequency of male patients was found to be twice that of females (sex ratio 2.00:1), indicating sensitivity of males to environmental factors.

Occupation

Frequency of agricultural laborers was found to be highly elevated in CML group (25.4%) when compared to that of control population (3.6%). Vojdani?et al. reported that pesticide exposure affected the functioning of the blood vascular system,[18] and improper use of pesticides was shown to induce neurological and hematological complications in individuals,[19] [20] which might be the reason for enhanced risk of CML development among agriculture laborers. The sex ratio was also found to be elevated among agricultural laborers and other laborers (working in factories, house construction, and other fields) (2.64:1 and 2.90:1, respectively) [Table 1], indicating that males exposed to pollutants may be at more risk for CML development compared to females.

Personal history of chronic myeloid leukemia patients

Diet

In the present study [Table 1], the frequency of vegetarians was found to be almost half (7.5%) in CML cases as compared to that of controls (18.6%). Further, higher mean age at onset of CML patients who were on vegetarian diet (41.48 ? 14.26 years) when compared to that of nonvegetarian CML patients (36.13 ? 12.56 years) confirmed the protective role of vegetarian diet reported by earlier studies.[21]

Smoking and/or alcoholic history

In our study, the frequency of males with smoking and alcoholic history was found to be elevated in CML group (28.8%) when compared to that of controls (17.8%) [Table 1]. Among the cases with this history, 14.4%, 5.76%, and 12.38% were found to be smokers, alcoholics, and both smokers and alcoholics, respectively, indicating that smoking alone or in combination with alcohol consumption might have confounded the risk for CML. These results were supported by the findings of Kabat?et al.[22] and Musselman?et al.[23]

Sokal, Hasford, and European Treatment and Outcome Study risk scores

Majority of the CML patients were in the high- and intermediate-risk groups of Sokal and Hasford scores (46.1% and 53.0%, respectively) [Table 2]. However, the frequency of patients was found to be reduced for EUTOS high-risk group (39.2%), for which scoring was based only on the basophil count and spleen size. Sex ratio was also elevated for the high-risk group of Hasford score (2.09:1), which was similar to the report of Berger?et al.,[24] where female patients were found to be more frequent in the low-risk groups of Sokal score.

Distribution of clinical characteristics of chronic myeloid leukemia patients

Phase of chronic myeloid leukemia

In the present study, 85.5% of the patients were found to be diagnosed in CP [Table 2], and 7.8% and 6.7% of patients were diagnosed in AP and BC, respectively. The sex ratio was highly elevated for the patients in BC (2.88:1), indicating that males were found to be more frequent in progression compared to females at the time of diagnosis.

Imatinib mesylate response

In general, 95% and 80% of the patients in early CP-CML were shown to achieve complete hematological response (CHR) and CCR, respectively, and these responses were found to be stable in most patients with a risk of relapse of 4%?6%/year.[25] For patients with advanced CML (AP or BC), achievement of CHR and major (complete and partial) cytogenetic response were shown to occur only in 25%?37% and 10%?30% of the patients, respectively.[10] In the present study, 65.7% of the CML patients were shown to achieve CHR. Nearly 1/3rd frequency of patients did not achieve HR (partial: 15.5% and poor: 18.8% of the patients) in time. CCR was observed in 59.8% of the CML cases, while 55.9?ses showed complete molecular response (CMR)/major molecular response which included the patients diagnosed or reported in all three phases of CML. The sex ratio was found to be highly elevated among poor responders with respect to all three types of responses monitored [Table 2], indicating the reduced response of male patients to treatment.

Phase versus imatinib mesylate response

About 72.1%, 65.23%, and 58.43% of the patients diagnosed in the CP were found to achieve CHR, CCR, and CMR, respectively, whereas only very few patients diagnosed in BC showed good responses. The frequency of patients diagnosed in AP with good drug response was also low when compared to patients in CP but higher when compared to those of BC [Table 3]. The results of the present study were found to be in accordance with the earlier studies by Kumar.[25]

Imatinib mesylate response with respect to the phase of chronic myeloid leukemia

Overall survival

In general, 90% of the people in CP were reported to live for 5 years or beyond, whereas patients were found to be alive for only 3?6 months rather than years if diagnosed in or progressed to BC.[26] In our study, no significant elevation in the sex ratio was found for the patients showing primary resistance (not able to achieve CCR within 6?12 months after the start of treatment), for the patients showing secondary resistance to IM (initial response to IM and later showing relapse), and for the relative 4-year overall survival of the patients. However, the mortality rate of patients as per the hospital records was found to be higher for the male population compared to the female population (4.02:1) [Table 4].

Survival rates of chronic myeloid leukemia patients and gender distribution

Correlation between clinical variables

Results of the test [Table 5] revealed that a negative correlation was observed between age at onset and white blood cell count/platelet count/EFS. Many reports indicated reduced response rates among the older patients,[27] [28] which might be one of the reasons for the faster progression of disease and reduced EFS rates among elderly patients than younger patients. All risk scores were found to be in positive correlation with each other. Importantly, EUTOS score showed a highly significant negative correlation with the relative 4-year overall survival rate of the CML patients. Further, the EFS rates showed a significant positive correlation with the

Correlation between the clinical variables among chronic myeloid leukemia cases

Cox regression analysis

In the present study, the analysis was done for 209 CML patients diagnosed in CP for whom the data on EFS rate were available [Table 6]. Sex of the patient was not found to have any effect on the EFS rate. However, the patients with early age at onset (<20 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_141_17#JR_28" xss=removed>29]

Cox regression analysis of clinical characteristics on event-free survival rate in chronic phase ? chronic myeloid leukemia

When the IM response was considered, patients who had not achieved HR had 2.10-fold increased risk for progression and shortened EFS rate. Further, cytogenetic partial and poor responders had significantly elevated risk for progression which suggests strong dependence of CML progression on IM response [Table 6]. Molecular response did not seem to have effect on the progression and EFS rate of CP-CML patients. Molecular response is based on the presence of BCR-ABL fusion gene, and majority of the patients were found to be with minimal residual disease containing detectable levels of BCR-ABL fusion gene on real-time PCR. These patients may not be showing any event of progression or death until and unless the BCR-ABL levels rise.

Conclusions

The association of male sex with occupation and area of living as observed in the present study strongly suggests the effect of interaction of environmental factors and inherent genetic susceptibility for the enhanced risk to CML development among males. In addition, elevated frequency of males with advanced phase of CML, high-risk scores, and poor-drug response observed in the present study also imply the genetic susceptibility of males for the enhanced risk of CML progression. Furthermore, the observation supported the earlier reports which found that the drug response of patients depend on their age at onset and phase of diagnosis, and the progression of disease in turn depends on the response to TKIs. Hence, treatment strategies may be planned by considering these factors for achieving better prognosis and long-term disease-free or overall survival among CML patients.

Conflict of Interest

There are no conflicts of interest.

Acknowledgment

This work was supported by the UGC-Dr. DS. Kothari Post Doctoral Fellowship Program to Dr. Manjula Gorre (F.4-2/2006 [BSR]/BL/14-15/0150). We sincerely thank Mr. Ramesh for his help in recording the patient?s clinical information.

• References